Telomere length is associated with increased risk of cutaneous melanoma: a Mendelian randomization study

The objective was to investigate the causal association between genetically predicted telomere length (TL) and cutaneous melanoma (CM) risk using Mendelian randomization (MR). This study utilized a two-sample MR and two large genome-wide association studies (GWAS) were used for instrumental variable (IV) selection to select single nucleotide polymorphisms at the genome-wide significance threshold (P < 5E-08) for TL. The IVs were then pruned for linkage disequilibrium and weak instrument bias. Summary statistics from a GWAS meta-analysis of CM were used as the outcome variable. The inverse variance weighted (IVW) method was used as the primary approach for overall causal estimation in MR, with sensitivity analyses performed to assess robustness. All statistical analyses were conducted in R studio.Results The MR analysis using two TL GWAS datasets revealed strong and consistent evidence that long TL is causally associated with an increased risk of CM. The analysis of the Codd et al. dataset found that long TL significantly predicted an elevated risk of CM (IVW OR = 2.411, 95% CI 2.092-2.780, P = 8.05E-34). Similarly, the analysis of the Li et al. dataset yielded consistent positive results across all MR methods, providing further robustness to the causal relationship (IVW OR = 2.324, 95% CI 1.516-3.565, P = 1.11E-04). The study provides evidence for a causal association between TL and CM susceptibility, indicating that longer TL increases the risk of developing CM and providing insight into the unique telomere biology in melanoma pathogenesis. Telomere maintenance pathways may be a potential target for preventing and treating CM.